FDA Regulatory and Compliance Monthly Recap — September 2017

• FDA finalizes guidance on considerations for use of real-world data, evidence in regulatory decision-making for medical devices
• FDA’s device regulator finalizes guidance on use of age, race and ethnicity in medical device trials
• FDA issues final guidance with recommendations on pre-market submissions and labeling for interoperable medical devices
• OPDP’s second warning letter in 2017 targets misleading opioid marketing

FDA finalizes guidance on considerations for use of real-world data, evidence in regulatory decision-making for medical devices

The guidance addresses the factors used in determining whether real-world data is appropriate to generate real-world evidence of sufficient quality for use in regulatory decision-making, including to support approvals or new indications for use. The guidance doesn’t mandate the use of RWD or limit other means of providing evidence.

The FDA finalized guidance on the use of real-world data (RWD) and associated real-world evidence (RWE) in regulatory decision-making for medical devices. The guidance defines RWD as data pertinent to patient health status or the delivery of healthcare, such as electronic health records or data from product registries. RWE is defined as the clinical evidence about the use and potential risks of a medical product resulting from an assessment of RWD. The guidance outlines the FDA’s approach to determining whether RWD are sufficient for generating the type of RWE that may be used in regulatory decision-making.

Though the guidance cautions that data collected during clinical care in the home setting may not have the same quality controls as clinical data, it notes that RWD may provide insight into the performance and clinical outcomes of medical device use. These data may be suitable to demonstrate compliance with regulatory requirements or to help the FDA in its decision-making process. Instances in which RWD and their corresponding RWE may be useful to decision-making include:

• New devices/indications: Devices are frequently used for purposes beyond their cleared or approved indications, but the information derived from such uses may not be realized because the data aren’t dealt with in such a way as to be useful for regulatory decision-making. Under the right conditions, RWE may be appropriate to support the clearance or approval of a new device or indication, or to supplement the total evidence needed to support such clearances or approvals.
• In lieu of clinical trials: Traditional clinical trials may not be practical in certain instances, and the analysis of RWD, using proper methods, could provide similar information with comparable characteristics to data derived from a clinical trial. Investigations using RWD may also provide data from a broader patient population, as clinical trials may be narrow in scope.
• Post-market surveillance: The capture of RWD may provide a useful tool for post-market safety surveillance and post-market generation of evidence supporting efficacy, which in turn could reduce the required pre-market data collection.

Since not all RWD are collected in a way that offers satisfactory reliability, the guidance states that the use of RWE for specific regulatory purposes will be assessed based on criteria exploring its overall relevance and reliability. The guidance outlines several relevance factors that will be considered in determining whether RWD are suitable for regulatory use, including the following:

• Data containing enough details to capture the use of the device and outcomes of interest in the appropriate population.
• Data elements available for analysis are able to address the specified question when proper analytical methods are used.
• The RWD and corresponding RWE are interpretable using informed clinical or scientific judgment (the guidance outlines several considerations for assessing this factor).

In terms of reliability, the guidance indicates the FDA will take into consideration data accrual, assurance and analytical approaches. The threshold for sufficient quality will vary based on the particular regulatory use of the evidence.

The guidance states that an investigational device exemption (IDE) likely won’t be needed for the collection of RWD for a legally marketed device if the device is used during the course of routine medical practice. However, if data are being used to determine the safety and efficacy of a device and the process for gathering said data would influence treatment decisions, an IDE may be needed.

FDA’s device regulator finalizes guidance on use of age, race and ethnicity in medical device trials

The CDRH finalized guidance to encourage medical device makers to collect and take into consideration data on age, ethnicity, race and associated covariates when designing trials. It discusses the recommended analyses of study subgroup data with a framework for considering demographic data when examining overall study outcomes.

The Center for Devices and Radiological Health (CDRH) published final guidance outlining the FDA’s expectations for patient enrollment, data analysis, and reporting of age, race and ethnicity in medical device studies. The guidance applies to devices that include clinical information in support of a 510(K), pre-market approval application, de novo request or humanitarian device exemption, as well as post-approval study submission or post-market surveillance studies.

When evaluating age, the guidance recommends investigating group subjects by age groups appropriate for the specific disease being studied, as standardized age categories may not be appropriate for all devices. The guidance suggests stratifying age (e.g., 65-74, ≥75 years) based on pertinent disease characteristics. It notes that the definition of a pediatric patient per 21 CFR 814.3(s) should be used, which defines a pediatric population as any patient less than 22 years of age. The guidance recommends that racial and ethnic data be captured as two distinct categories, as patients may self-identify as both (e.g., Hispanic-White, Hispanic-Black). It notes, however, that more granular data may be important depending on the disease or condition being studied and the specific patient population. The categories and identification method should be described in the study protocol, particularly for studies that involve sites outside the U.S.

The guidance recommends that medical device sponsors develop a strategy to enroll diverse populations that reflect the intended population for use, with pre-specified plans for subgroup analyses. It cautions that unplanned subgroup analyses are generally not considered sufficient to support labeling statements regarding safety or efficacy. To ensure appropriate enrollment is reached and an unbiased estimate of treatment effect in the general population, the guidance recommends that sponsors consider age-, race- and ethnicity-specific prevalence of the disease being studied, as well as treatment patterns. It may also be helpful to examine the proportions of age-, race- and ethnicity-specific subgroups in prior studies of the target disease and any known medical differences in outcomes related to these subgroups. This information should be included in the investigational plan for IDE studies. It should also be summarized in study protocol and included as part of marketing applications as well as post-market reports.

The guidance provides recommendations to increase enrollment of subgroups, including by using an array of investigational sites, using alternative communication strategies for recruitment, and revising enrollment criteria to ensure age-, race- and ethnicity-specific subgroups meet criteria for study entry. The guidance recommends that in assessing the study results, sponsors discuss how any known, clinically meaningful age-, race- and ethnicity-specific differences may impact the benefit-risk profile. The guidance also recommends that sponsors consider whether outstanding questions warrant post-market study in specific subgroups.

The guidance further recommends that sponsors submit and publicly report by subgroup the number and proportion of subjects who were treated with the device. During the IDE stage, demographic data should be submitted as part of the annual progress report. During the pre-market period, information should be included in 510(K) submissions in sections to address clinical trial results, including the labeling. In the post-market period, demographic information should be included in interim reports and the final report for any required post-market studies.

FDA issues final guidance with recommendations on pre-market submissions and labeling for interoperable medical devices

This guidance provides manufacturers with design considerations when developing interoperable medical devices, and recommendations regarding information to include in pre-market submissions and device labeling.

According to the guidance, manufacturers should consider the following goals in their effort to provide a reasonable assurance of safety and effectiveness of interoperable medical devices:

• Design systems with interoperability as an objective.
• Conduct appropriate verification, validation and risk management activities.
• Specify the relevant functional, performance and interface characteristics in a user-available manner such as labeling.

The FDA notes that patient and operator safety is the most important consideration for medical devices involved in interoperable systems – specifically, the ability of such devices to safely and effectively exchange information with other medical devices and technology. The guidance recommends that the following factors be considered, then tailored based on each device’s interface technology and intended use:

1. The purpose of the electronic interface: Manufacturers should consider the purpose for each of the electronic interfaces, including the types of data exchanges taking place (e.g., sending, receiving, issue command and control). The purpose should be taken into consideration, both when designing the device and when developing associated instructions. The labeling should contain enough information to enable anticipated users to connect to and use the device and interface as intended.
2. The anticipated users: Manufacturers may wish to change the design of the device or the intended interoperability scenarios, or include warnings, precautions or contraindications in their labeling to manage risks based on the device’s anticipated users. Examples of users include biomedical engineers, home healthcare users, IT professionals, system integrators, system designers, patients, researchers and medical device designers.
3. Risk management: The guidance recommends that as part of their risk management strategy, manufacturers establish, document and maintain an ongoing process for identifying hazards, evaluating and controlling associated risks, and monitoring the controls’ effectiveness throughout the medical device life cycle.
4. Verification and validation: Manufacturers should establish, maintain and implement an appropriate verification and validation process to ensure devices work correctly throughout their entire life cycle. The process should be developed based on the level of risks associated with the device.
5. Labeling considerations: Manufacturers should include enough information for all users to connect safely to the interface for its intended purpose. Appropriate labeling options should be determined based on user and risk analysis profiles.
6. Use of consensus standards: For elements of the interface that use a consensus standard, it may be sufficient to demonstrate conformance to that standard. The document encourages the use of FDA-recognized consensus standards applicable to the development and design of interoperable medical devices.

The guidance recognizes that not all interoperable medical devices require pre-market submission to the FDA, and provides examples of the types of devices that do require a submission. It further states that the amount of documentation required for each submission can vary based on a number of factors, including a device’s associated risks, purpose, anticipated users and intended use.

The FDA says it is cognizant that the industry may need up to 60 days to carry out activities to operationalize the policies outlined in the guidance document. It further specifies that “if new information regarding device interoperability as outlined in this guidance is not included in a premarket submission received by FDA before or up to 60 days after the publication of this guidance, CDRH staff does not generally intend to request such information during the review of the submission.”

OPDP’s second warning letter in 2017 targets misleading opioid marketing

The letter, sent to Canadian drugmaker Cipher Pharmaceuticals, takes issue with promotional material for an opioid that left out important information about the drug’s use and risks. The OPDP said the material gives a misleading impression of the drug.

The Office of Prescription Drug Promotion (OPDP) sent a warning letter on August 24 to Canadian drugmaker Cipher Pharmaceuticals raising concerns about its marketing material for ConZip, a combination immediate- and extended-release opioid. The letter raises concerns about a professional detail aid, submitted by license holder Vertical Pharmaceuticals under a Form FDA 2253, that leaves out important risk information and other material facts.

ConZip is approved for the management of severe pain when alternative treatment options are inadequate, but not as an as-needed pain medication. The drug contains boxed warnings pertaining to addiction, abuse and misuse, as well as other risks, such as the potential for respiratory depression. The marketing materials portray the drug as effective for all-day pain relief and as being indicated for moderate to moderately severe chronic pain, but fail to present risk information. This gives a misleading impression about the treatment’s safety – a particularly concerning fact given the current opioid epidemic, the OPDP notes. The professional detail aid also failed to disclose key aspects of the indication and its limitation of use by omitting the fact that ConZip is indicated only when alternatives aren’t sufficient and not as an as-needed treatment.

Based on the violations, the OPDP is requesting that Cipher immediately stop misbranding the drug and provide a written response outlining all promotional materials that contain such representations of the treatment. Given the seriousness of the violations, the OPDP is also asking that Cipher provide a comprehensive plan of action to disseminate truthful, non-misleading and complete corrective messages to the healthcare practitioners that received the professional detail aid. The letter recommends that the corrective messaging include a description of the violative communications and the corrections, free from promotional claims and distributed using the same media.